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2. The natural history of classic galactosemia: lessons from the GalNet registry

Author

Rubio-Gozalbo, M. E., Haskovic, M., Bosch, A. M., Burnyte, B., Coelho, A. I., Cassiman, D., Couce, M. L., Dawson, C., Demirbas, D., Derks, T., Eyskens, F., Forga, M. T., Grunewald, S., Häberle, J., Hochuli, M., Hubert, A., Huidekoper, H. H., Janeiro, P., Kotzka, J., Knerr, I., Labrune, P., Landau, Y. E., Langendonk, J. G., Möslinger, D., Müller-Wieland, D., Murphy, E., Õunap, K., Ramadza, D., Rivera, I. A., Scholl-Buergi, S., Stepien, K. M., Thijs, A., Tran, C., Vara, R., Visser, G., Vos, R., de Vries, M., Waisbren, S. E., Welsink-Karssies, M. M., Wortmann, S. B., Gautschi, M., Treacy, E. P., and Berry, G. T.

Published
2019
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9. Early prediction of phenotypic severity in Citrullinemia Type 1

Author

Zielonka, Matthias, Kölker, Stefan, Gleich, Florian, Stützenberger, Nicolas, Nagamani, Sandesh C S, Gropman, Andrea L, Hoffmann, Georg F, Garbade, Sven F, Posset, Roland, Sarajlija, Adrijan, Skouma, Anastasia, Schulze, Andreas, Garcia‐Cazorla, Angeles, Lund, A M, Jalan, Anil, Morris, Andrew, Dionisi‐Vici, Carlo, De Laet, Corinne, Leão Teles, Elisa, Diaz, G A, Berry, G T, Payan‐Walters, Irma, Blasco‐Alonso, Javier, Seminara, Jennifer, Bedoyan, Jirair K, Merritt, J Lawrence, Burrage, Lindsay C, Yudkoff, Marc, Schiff, Manuel, Baumgartner, Matthias R, et al, University of Zurich, and Posset, Roland

Subjects
2728 Neurology (clinical), 10036 Medical Clinic, 2800 General Neuroscience, 610 Medicine & health
Published
2019

15. Early prediction of phenotypic severity in Citrullinemia Type 1

Author

Zielonka, Matthias; https://orcid.org/0000-0001-9653-2914, Kölker, Stefan, Gleich, Florian, Stützenberger, Nicolas, Nagamani, Sandesh C S, Gropman, Andrea L, Hoffmann, Georg F, Garbade, Sven F, Posset, Roland; https://orcid.org/0000-0002-2249-3980, Sarajlija, Adrijan, Skouma, Anastasia, Schulze, Andreas, Garcia‐Cazorla, Angeles, Lund, A M, Jalan, Anil, Morris, Andrew, Dionisi‐Vici, Carlo, De Laet, Corinne, Leão Teles, Elisa, Diaz, G A, Berry, G T, Payan‐Walters, Irma, Blasco‐Alonso, Javier, Seminara, Jennifer, Bedoyan, Jirair K, Merritt, J Lawrence, Burrage, Lindsay C, Yudkoff, Marc, Schiff, Manuel, Baumgartner, Matthias R; https://orcid.org/0000-0002-9270-0826, et al, Zielonka, Matthias; https://orcid.org/0000-0001-9653-2914, Kölker, Stefan, Gleich, Florian, Stützenberger, Nicolas, Nagamani, Sandesh C S, Gropman, Andrea L, Hoffmann, Georg F, Garbade, Sven F, Posset, Roland; https://orcid.org/0000-0002-2249-3980, Sarajlija, Adrijan, Skouma, Anastasia, Schulze, Andreas, Garcia‐Cazorla, Angeles, Lund, A M, Jalan, Anil, Morris, Andrew, Dionisi‐Vici, Carlo, De Laet, Corinne, Leão Teles, Elisa, Diaz, G A, Berry, G T, Payan‐Walters, Irma, Blasco‐Alonso, Javier, Seminara, Jennifer, Bedoyan, Jirair K, Merritt, J Lawrence, Burrage, Lindsay C, Yudkoff, Marc, Schiff, Manuel, Baumgartner, Matthias R; https://orcid.org/0000-0002-9270-0826, and et al

Abstract

Objective Citrullinemia type 1 (CTLN1) is an inherited metabolic disease affecting the brain which is detectable by newborn screening. The clinical spectrum is highly variable including individuals with lethal hyperammonemic encephalopathy in the newborn period and individuals with a mild‐to‐moderate or asymptomatic disease course. Since the phenotypic severity has not been predictable early during the disease course so far, we aimed to design a reliable disease prediction model. Methods We used a newly established mammalian biallelic expression system to determine residual enzymatic activity of argininosuccinate synthetase 1 (ASS1; OMIM #215700) in 71 individuals with CTLN1, representing 48 ASS1 gene variants and 50 different, mostly compound heterozygous combinations in total. Residual enzymatic ASS1 activity was correlated to standardized biochemical and clinical endpoints available from the UCDC and E‐IMD databases. Results Residual enzymatic ASS1 activity correlates with peak plasma ammonium and L‐citrulline concentrations at initial presentation. Individuals with 8% of residual enzymatic ASS1 activity or less had more frequent and more severe hyperammonemic events and lower cognitive function than those above 8%, highlighting that residual enzymatic ASS1 activity allows reliable severity prediction. Noteworthy, empiric clinical practice of affected individuals is in line with the predicted disease severity supporting the notion of a risk stratification‐based guidance of therapeutic decision‐making based on residual enzymatic ASS1 activity in the future. Interpretation Residual enzymatic ASS1 activity reliably predicts the phenotypic severity in CTLN1. We propose a new severity‐adjusted classification system for individuals with CTLN1 based on the activity results of the newly established biallelic expression system.

Published
2019

16. The natural history of classic galactosemia: lessons from the GalNet registry

Author

Universidade de Santiago de Compostela. Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía e Obstetricia, e Pediatría, Rubio-Gozalbo, M. E., Haskovic, M., Bosch, A. M., Burnyte, B., Coelho, A. I., Cassiman, D., Couce Pico, María de la Luz, Dawson, C., Demirbas, D., Derks, T., Eyskens, F., Forga, M. T., Grunewald, S., Häberle, J., Hochuli, M., Hubert, A., Huidekoper, H. H., Janeiro, P., Kotzka, J., Knerr, I., Labrune, P., Landau, Y. E., Langendonk, J. G., Möslinger, D., Müller-Wieland, D., Murphy, E., Õunap, K., Ramadza, D., Rivera, I. A., Scholl-Buergi, S., Stepien, K. M., Thijs, A., Tran, C., Vara, R., Visser, G., Vos, R., de Vries, M., Waisbren, S. E., Welsink-Karssies, M. M., Wortmann, S. B., Gautschi, M., Treacy, E. P., Berry, G. T., Universidade de Santiago de Compostela. Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía e Obstetricia, e Pediatría, Rubio-Gozalbo, M. E., Haskovic, M., Bosch, A. M., Burnyte, B., Coelho, A. I., Cassiman, D., Couce Pico, María de la Luz, Dawson, C., Demirbas, D., Derks, T., Eyskens, F., Forga, M. T., Grunewald, S., Häberle, J., Hochuli, M., Hubert, A., Huidekoper, H. H., Janeiro, P., Kotzka, J., Knerr, I., Labrune, P., Landau, Y. E., Langendonk, J. G., Möslinger, D., Müller-Wieland, D., Murphy, E., Õunap, K., Ramadza, D., Rivera, I. A., Scholl-Buergi, S., Stepien, K. M., Thijs, A., Tran, C., Vara, R., Visser, G., Vos, R., de Vries, M., Waisbren, S. E., Welsink-Karssies, M. M., Wortmann, S. B., Gautschi, M., Treacy, E. P., and Berry, G. T.

Abstract

Background: Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients. Methods: Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018. Results: Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome. Conclusion: This study describes the natural history of classic galactosemia based on the hitherto largest data set.

Published
2019

17. The natural history of classic galactosemia: Lessons from the GalNet registry

Author

Infectieziekten onderzoek3 (Bogaert), UMC Utrecht, Metabole ziekten patientenzorg, HAG Hart- Vaatziekten, Other research (not in main researchprogram), JC onderzoeksprogramma Cardiovasculaire Epidemiologie, AIOS Psychiatrie, Rubio-Gozalbo, M. E., Haskovic, M., Bosch, A. M., Burnyte, B., Coelho, A. I., Cassiman, D., Couce, M. L., Dawson, C., Demirbas, D., Derks, T., Eyskens, F., Forga, M. T., Grunewald, S., Häberle, J., Hochuli, M., Hubert, A., Huidekoper, H. H., Janeiro, P., Kotzka, J., Knerr, I., Labrune, P., Landau, Y. E., Langendonk, J. G., Möslinger, D., Müller-Wieland, D., Murphy, E., Õunap, K., Ramadza, D., Rivera, I. A., Scholl-Buergi, S., Stepien, K. M., Thijs, A., Tran, C., Vara, R., Visser, G., Vos, R., De Vries, M., Waisbren, S. E., Welsink-Karssies, M. M., Wortmann, S. B., Gautschi, M., Treacy, E. P., Berry, G. T., Infectieziekten onderzoek3 (Bogaert), UMC Utrecht, Metabole ziekten patientenzorg, HAG Hart- Vaatziekten, Other research (not in main researchprogram), JC onderzoeksprogramma Cardiovasculaire Epidemiologie, AIOS Psychiatrie, Rubio-Gozalbo, M. E., Haskovic, M., Bosch, A. M., Burnyte, B., Coelho, A. I., Cassiman, D., Couce, M. L., Dawson, C., Demirbas, D., Derks, T., Eyskens, F., Forga, M. T., Grunewald, S., Häberle, J., Hochuli, M., Hubert, A., Huidekoper, H. H., Janeiro, P., Kotzka, J., Knerr, I., Labrune, P., Landau, Y. E., Langendonk, J. G., Möslinger, D., Müller-Wieland, D., Murphy, E., Õunap, K., Ramadza, D., Rivera, I. A., Scholl-Buergi, S., Stepien, K. M., Thijs, A., Tran, C., Vara, R., Visser, G., Vos, R., De Vries, M., Waisbren, S. E., Welsink-Karssies, M. M., Wortmann, S. B., Gautschi, M., Treacy, E. P., and Berry, G. T.

Published
2019

24. Targeted exome sequencing of suspected mitochondrial disorders

Author

Lieber, D. S., primary, Calvo, S. E., additional, Shanahan, K., additional, Slate, N. G., additional, Liu, S., additional, Hershman, S. G., additional, Gold, N. B., additional, Chapman, B. A., additional, Thorburn, D. R., additional, Berry, G. T., additional, Schmahmann, J. D., additional, Borowsky, M. L., additional, Mueller, D. M., additional, Sims, K. B., additional, and Mootha, V. K., additional

Published
2013
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25. The 21q22.1 STS marker, VN02 (EST00541 cDNA), is part of the 3' sequence of the human Na+/myo-inositol cotransporter (SLC5A3) gene

Author

Berry, G. T., Mallee, J. J., Blouin, J. -L, and Stylianos Antonarakis

Subjects
Genetic Markers, DNA, Complementary, Base Sequence, Symporters, Chromosomes, Human, Pair 21, Molecular Sequence Data, Gene Expression, Membrane Proteins, DNA, Complementary/genetics, Heat-Shock Proteins/ genetics, Bacteriophages/genetics, Polymerase Chain Reaction, Chromosomes, Human, Pair 21/ genetics, Genes, Humans, ddc:576.5, Bacteriophages, Carrier Proteins, Carrier Proteins/ genetics, Heat-Shock Proteins, DNA Primers
Abstract

The human osmoregulatory Na+/myo-inositol cotransporter gene (SLC5A3) was recently cloned and localized to the region of 21q22. Fine mapping of this gene was accomplished by identifying YAC clones that contain SLC5A3 and utilizing known STS markers for 21q22.1 and 21q22.2 sub-bands that map to the positive YAC clones. Two bacteriophage P1 clones containing the SLC5A3 gene gave a positive PCR product when screened with the 21q22.1 marker VN02, an expressed sequence tag (EST00541). Through DNA sequence analysis, it was determined that this STS marker if part of the 3' untranslated region of the SLC5A3 gene.

Published
1996

26. A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype

Author

Shih, V E, Fringer, J M, Mandell, R, Kraus, J P, Berry, G T, Heidenreich, R A, Korson, M S, Levy, H L, and Ramesh, V

Subjects
Adult, Male, Base Sequence, DNA Mutational Analysis, Molecular Sequence Data, Cystathionine beta-Synthase, Pyridoxine, Exons, Middle Aged, Polymerase Chain Reaction, Cell Line, Phenotype, Humans, Point Mutation, Female, Homocystinuria, Child, Polymorphism, Single-Stranded Conformational, Research Article
Abstract

Cystathionine beta-synthase (CBS) deficiency is an autosomal recessive disorder characterized by homocystinuria and multisystem clinical disease. Patients responsive to pyridoxine usually have a milder clinical phenotype than do nonresponsive patients, and we studied the molecular pathology of this disorder in an attempt to understand the molecular basis of the clinical variation. We previously reported a T833C transition in exon 8 causing a substitution of threonine for isoleucine at codon 278 (I278T). By PCR amplification and sequencing of exon 8 from genomic DNA we have now detected the I278T mutation in 7 of 11 patients with in vivo pyridoxine responsiveness and in 0 of 27 pyridoxine-nonresponsive patients. Two pyridoxine-responsive patients are homozygous and five are heterozygous for I278T. We have now observed the I278T mutation in 41% (9 of 22) of the independent alleles in pyridoxine-responsive patients of varied ethnic backgrounds. In two of the compound heterozygotes we identified a novel mutation (G139R and E144K) in the other allele. The finding that the two patients who are homozygous for I278T have only ectopia lentis and mild bone demineralization suggests that this mutation is associated with both in vivo pyridoxine responsiveness and mild clinical disease. Compound heterozygous patients who have one copy of this missense mutation are likely to retain some degree of pyridoxine responsiveness.

Published
1995

30. IP3 accumulation and/or inositol depletion: two downstream lithium's effects that may mediate its behavioral and cellular changes

Author

Sade, Y, Toker, L, Kara, N Z, Einat, H, Rapoport, S, Moechars, D, Berry, G T, Bersudsky, Y, and Agam, G

Abstract

Lithium is the prototype mood stabilizer but its mechanism is still unresolved. Two hypotheses dominate—the consequences of lithium's inhibition of inositol monophosphatase at therapeutically relevant concentrations (the ‘inositol depletion' hypothesis), and of glycogen-synthase kinase-3. To further elaborate the inositol depletion hypothesis that did not decisively determine whether inositol depletion per se, or phosphoinositols accumulation induces the beneficial effects, we utilized knockout mice of either of two inositol metabolism-related genes—IMPA1 or SMIT1, both mimic several lithium's behavioral and biochemical effects. We assessed in vivo, under non-agonist-stimulated conditions, 3H-inositol incorporation into brain phosphoinositols and phosphoinositides in wild-type, lithium-treated, IMPA1 and SMIT1 knockout mice. Lithium treatment increased frontal cortex and hippocampal phosphoinositols labeling by several fold, but decreased phosphoinositides labeling in the frontal cortex of the wild-type mice of the IMPA1 colony strain by ~50%. Inositol metabolites were differently affected by IMPA1 and SMIT1 knockout. Inositoltrisphosphate administered intracerebroventricularly affected bipolar-related behaviors and autophagy markers in a lithium-like manner. Namely, IP3 but not IP1 reduced the immobility time of wild-type mice in the forced swim test model of antidepressant action by 30%, an effect that was reversed by an antagonist of all three IP3 receptors; amphetamine-induced hyperlocomotion of wild-type mice (distance traveled) was 35% reduced by IP3 administration; IP3 administration increased hippocampal messenger RNA levels of Beclin-1 (required for autophagy execution) and hippocampal and frontal cortex protein levels ratio of Beclin-1/p62 by about threefold (p62 is degraded by autophagy). To conclude, lithium affects the phosphatidylinositol signaling system in two ways: depleting inositol, consequently decreasing phosphoinositides; elevating inositol monophosphate levels followed by phosphoinositols accumulation. Each or both may mediate lithium-induced behavior.

Published
2016
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39. Fatal hyperammonemia after orthotopic lung transplantation.

Author

Lichtenstein, Gary R., Nunes, Frederick A., Lichtenstein, G R, Yang, Y X, Nunes, F A, Lewis, J D, Tuchman, M, Tino, G, Kaiser, L R, Palevsky, H I, Kotloff, R M, Furth, E E, Bavaria, J E, Stecker, M M, Kaplan, P, and Berry, G T

Subjects
LUNG transplantation, AMMONIUM, PHYSIOLOGY
Abstract

Background: A case of fatal hyperammonemia complicating orthotopic lung transplantation was previously reported.Objective: To describe the incidence, clinical features, and treatment of hyperammonemia associated with orthotopic lung transplantation.Design: Retrospective cohort analysis.Setting: Academic medical center and lung transplantation center in Philadelphia, Pennsylvania.Patients: 145 sequential adult patients who underwent orthotopic lung transplantation.Measurements: Plasma ammonium levels.Results: Six of the 145 patients who had had orthotopic lung transplantation developed hyperammonemia, all within the first 26 days after transplantation. The 30-day post-transplantation mortality rate was 67% for patients with hyperammonemia compared with 17% for those without hyperammonemia (P = 0.01). Development of major gastrointestinal complications (P = 0.03), use of total parenteral nutrition (P < 0.001), and lung transplantation for primary pulmonary hypertension (P = 0.045) were associated with hyperammonemia.Conclusions: Hyperammonemia is a potentially fatal event occurring after orthotopic lung transplantation. It is associated with high nitrogen load, concurrent medical stressors, primary pulmonary hypertension, and hepatic glutamine synthetase deficiency. [ABSTRACT FROM AUTHOR]

Published
2000
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40. Murine chromosome 16 telomeric region, homologous with human chromosome 21q22, contains the osmoregulatory Na[sup +] /myo-inositol cotransporter (SLC5A3) gene.

Author

McVeigh, K. E., Mallee, J. J., Lucente, A., Barnoski, B. L., Wu, S., and Berry, G. T.

Subjects
CHROMOSOMES, HOMOLOGY (Biology), TELOMERES, AMINO acids, TRISOMY, FLUORESCENCE in situ hybridization
Abstract

The murine Na[sup +] /myo-inositol cotransporter (SLC5A3) gene (Slc5a3) was cloned, the restriction sites mapped, and the coding region sequenced. Similar to other mammalian counterparts, including human, the gene has a single coding exon, with an open reading frame of 2.2 kb. The predicted protein of 718 amino acids is also highly conserved, compared to other mammalian homologs. Using fluorescence in situ hybridization, Slc5a3 was localized to the telomeric region of mouse chromosome 16, which is syntenic to human chromosome 21q22. An increased Slc5a3 copy number may explain the increased levels of myo-inositol in the brains of trisomy 16 mice and the increased rate of transport of myo-inositol into cultured neurons derived from trisomy 16 mice. Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Published
2000
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41. 1H MR spectroscopy of the basal ganglia in childhood: a semiquantitative analysis.

Author

Lam, W. W. M., Wang, Z. J., Zhao, H., Berry, G. T., Kaplan, P., Gibson, J., Kaplan, B. S., Bilaniuk, L. T., Hunter, J. V., Haselgrove, J. C., and Zimmermann, R. A.

Abstract

Proton MR spectra of the basal ganglia were obtained from 28 patients, 24 male and 14 female, median age 16.3 months (5 weeks to 31 years). They included 17 patients with normal MRI of the basal ganglia without metabolic disturbance (control group) and 11 patients with various metabolic diseases: one case each of high serum sodium and high serum osmolarity, cobalamin C deficiency, Leigh disease, Galloway-Mowat syndrome, Pelizaeus-Merzbacher disease, hemolytic-uremic syndrome and Wilson disease and two cases of Alagille syndrome and methylmalonic acidemia with abnormal MRI of the basal ganglia or blood or urine analysis (abnormal group). The MR spectrum was measured by using STEAM. The MR-visible water content of the region of interest was obtained. Levels of myoinositol, choline, creatine and N -acetylaspartate were measured using a semiquantitative approach, with absolute reference calibration. In the control group, there was a gradual drop of water content over the first year of life; N -acetylaspartate, creatine and myoinositol levels showed no significant change with age, in contrast to the occipital, parietal and cerebellar regions. Choline showed a gradual decrease for the first 2 years of life and then remained fairly constant. In the abnormal group the water content was not significantly different. N -Acetylaspartate was decreased in patients with high serum sodium and high serum osmolarity, cobalamin C deficiency, Leigh disease and one case of methylmalonic acidemia. Decreased creatine was also found in Leigh disease, and decreased choline in Galloway-Mowat syndrome and Wilson disease. Myoinositol was elevated in the patient with abnormally high serum sodium, and decreased in the hemolytic-uremic syndrome. [ABSTRACT FROM AUTHOR]

Published
1998
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42. Elevated methylmalonic acid and total homocysteine levels show high prevalence of vitamin B12 deficiency after gastric surgery.

Author

Sumner AE, Chin MM, Abrahm JL, Berry GT, Gracely EJ, Allen RH, Stabler SP, Sumner, A E, Chin, M M, Abrahm, J L, Berry, G T, Gracely, E J, Allen, R H, and Stabler, S P

Abstract

Objective: To determine the prevalence of vitamin B12 deficiency in patients who have had gastric surgery.Design: Cross-sectional study.Setting: Philadelphia Veterans Affairs Medical Center.Participants: 61 patients who had had gastric surgery and 107 controls.Measurements: Serum levels of vitamin B12, folate, methylmalonic acid, and total homocysteine measured before and after treatment in participants with vitamin B12 deficiency. Vitamin B12 deficiency was defined as one of the following: 1) a serum vitamin B12 level less than 221 pmol/L and an elevated methylmalonic acid level; 2) a serum vitamin B12 level less than 221 pmol/L and an elevated total homocysteine level that decreased with vitamin B12 treatment; or 3) in patients unavailable for treatment, a serum vitamin B12 level less than 221 pmol/L, a folate level greater than 9 nmol/L, and an elevated total homocysteine level.Results: Study patients and controls were similar in age, sex, and racial distribution. Nineteen patients (31%) and 2 controls (2%) had vitamin B12 deficiency (P < 0.001). Twelve (63%) of the 19 vitamin B12-deficient patients had elevated total homocysteine levels. In all participants with vitamin B12 deficiency who received treatment (15 of 21), methylmalonic acid and total homocysteine levels decreased substantially, confirming the deficiency before treatment.Conclusion: Patients who have had gastric surgery have a high prevalence of vitamin B12 deficiency. Prompt recognition and treatment of the deficiency with resultant normalization of elevated total homocysteine and methylmalonic acid levels may prevent the development of cardiovascular, hematologic, and neurologic abnormalities. Our data support both frequent screening and vitamin B12 replacement therapy in patients who have had gastric surgery and have serum vitamin B12 levels less than 221 pmol/L. [ABSTRACT FROM AUTHOR]

Published
1996
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43. Abnormal Galactosylation of Complex Carbohydrates in Cultured Fibroblasts from Patients with Galactose1-Phosphate Uridyltransferase Deficiency

Author

ORNSTEIN, K. S., McGUIRE, E. J., BERRY, G. T., ROTH, S., and SEGAL, S.

Abstract

An abnormality in galactosylation of complex carbohydrates may be important in the pathogenesis of the long-term complications of classic (galactose-1-phosphate uridyltransferase-deficient) galactosemia. The ability of nine galactosemic fibroblast preparations to be galactosylated with a purified galactosyltransferase was measured as an indicator of vacant sites where galactose would normally reside. The amount of galactose transferred to cell protein from galactosemic patients was significantly higher than that transferred to a group of seven controls (p< 0.005). Galactosyltransferase activity of the galactosemic cell preparation toward N-acetylglucosamine was also significantly higher than normal (p< 0.01), and there was a linear relationship between these two parameters in galactosemic but not normal cells. These findings suggest that there is defective galactosylation of galactosemic cell complex carbohydrates and that such cells increase their galactosyltransferase levels in an attempt to compensate for the defect. Defective galactosylation may be implicated as an etiologic factor in complications observed in galactosemic patients even when treated with galactose-re-stricted diets.

Published
1992

44. The Effect of Glucose and Galactose Toxicity on Myoinositol Transport and Metabolism in Human Skin Fibroblasts in Culture

Author

BERRY, G. T., PRANTNER, J. E., STATES, B., and YANDRASITZ, J. R.

Abstract

Myo-inositol transport and metabolism were studied in cultured human skin fibroblasts exposed to potentially toxic levels of glucose or galactose. Although variable among 11 different cell lines, the myo-inositol level in confluent cells, ranging from 10–50 nmol/mg protein, was constant with passage. A high-affinity transport system for myo-inositol had an apparent K, of 55 μM and Vmaxof 16 pmol/min/mg protein. No obvious relationship existed between cellular levels and transport capacity. Dependency on sodium was complex. When medium sodium was lowered to 23 mM, myo-inositol uptake ceased after about 1 h. However, the initial rate of myo-inositol uptake only showed a sodium dependence at low myo-inositol concentrations. Both phloretin and phloridzin inhibited myo-inositol uptake. Phloridzin had a K1of 60 μM, and phloretin was either a noncompetitive or uncompetitive inhibitor. Glucose and galactose were only weak competitive inhibitors, with a K1of 30 mM and 65 mM, respectively. After 24 h of incubation with myo-[2-3H]inositol, only 10 of the total cell label was incorporated into phospholipid. Compared with control media with 5 mM glucose, the incubation of confluent cells in media with 20 mM glucose had little effect on intracellular glucose and sorbitol, whereas cells incubated in control media supplemented with 5 mM galactose showed a large increase in galactose and polyol levels. In media with more than 200 μM of myo-inositol, neither treatment had an effect on wyo-inositol levels after 24 h. The uptake and incorporation of 11 μM myo-[2-3H]inositol and incorporation into phospholipid were studied after cells had been previously exposed for 24 to 48 h to media supplemented with 15 mM glucose or galactose. Compared with controls, fibroblasts with a 24-h exposure to 20 mM glucose showed a 10 decrease in myo-inositol uptake. When the exposure was extended to 48 h, preconditioning with galactose as well as glucose elicited the same 10 reduction in uptake. Phosphoinositide labeling in fibroblasts exposed to 20 mM glucose was reduced in parallel. These cells offer a unique opportunity for the study of sugar toxicity in human tissue: they can be exposed to high levels of glucose without significant glucose or polyol accumulation or can be made to accumulate polyol by exposure to moderate levels of galactose. The expression of a hexose-induced reduction in myo-inositol transport required 24 to 48 h of exposure of the fibroblasts to elevated concentrations of glucose or galactose and may not be related to a competitive inhibitory effect of these sugars on transport.

Published
1994

45. Transcription of the sodium/myo-inositol cotransporter gene is regulated by multiple tonicity-responsive enhancers spread over 50 kilobase pairs in the 5'-flanking region.

Author

Rim, J S, Atta, M G, Dahl, S C, Berry, G T, Handler, J S, and Kwon, H M

Abstract

The sodium/myo-inositol cotransporter is a plasma membrane protein responsible for concentrative cellular accumulation of myo-inositol in a variety of tissues. When cells in kidney and brain are exposed to a hyperosmolar salt condition (hypertonicity) due to the operation of urinary concentration mechanism and pathological conditions, respectively, they survive the stress of hypertonicity by raising the cellular concentration of myo-inositol. Transcription of the sodium/myo-inositol cotransporter gene is markedly stimulated in response to hypertonicity, leading to an increase in the activity of the cotransporter, which in turn drives the osmoprotective accumulation of myo-inositol. To understand the molecular mechanisms by which hypertonicity stimulates transcription, we analyzed the 5'-flanking region of the cotransporter gene for cis-acting regulatory sequences. We identified five tonicity-responsive enhancers that are scattered over 50 kilobase pairs. All the enhancers are variations of the same type of enhancer interacting with the transcription factor named tonicity-responsive enhancer binding protein. In vivo methylation experiments demonstrated that exposure of cells to hypertonicity increases the binding of tonicity-responsive enhancer binding protein to the enhancer sites, indicating that all of these enhancers are involved in the transcriptional stimulation. We conclude that the sodium/myo-inositol cotransporter gene is regulated by a large region (approximately 50 kilobase pairs) upstream of the gene.

Published
1998

48. The adult galactosemic phenotype

Author

Waisbren, S. E., Potter, N. L., Gordon, C. M., Green, R. C., Greenstein, P., Gubbels, C. S., Estela Rubio-Gozalbo, M., Schomer, D., Welt, C., Anastasoaie, V., Anna, K. D., Gentile, J., Guo, C. Y., Hecht, L., Jackson, R., Jansma, Bernadette M., Li, Y., Lip, V., Murray, M., Power, L., Quinn, N., Rohr, F., Skinder-Meredith, A., Inge Timmers, Tunick, R., Wessel, A., Levy, H., Elsas, L., Berry, G. T., Kindergeneeskunde, Cognitive Neuroscience, and RS: FPN CN 7

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